Displaying publications 1 - 20 of 29 in total

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  1. Weniger BG, Takebe Y, Ou CY, Yamazaki S
    AIDS, 1994;8 Suppl 2:S13-28.
    PMID: 7857556
  2. Tee KK, Kusagawa S, Li XJ, Onogi N, Isogai M, Hase S, et al.
    PLoS One, 2009;4(8):e6666.
    PMID: 19688091 DOI: 10.1371/journal.pone.0006666
    A growing number of emerging HIV-1 recombinants classified as circulating recombinant forms (CRFs) have been identified in Southeast Asia in recent years, establishing a molecular diversity of increasing complexity in the region. Here, we constructed a replication-competent HIV-1 clone for CRF33_01B (designated p05MYKL045.1), a newly identified recombinant comprised of CRF01_AE and subtype B. p05MYKL045.1 was reconstituted by cloning of the near full-length HIV-1 sequence from a newly-diagnosed individual presumably infected heterosexually in Kuala Lumpur, Malaysia. The chimeric clone, which contains the 5' LTR (long terminal repeat) region of p93JP-NH1 (a previously isolated CRF01_AE infectious clone), showed robust viral replication in the human peripheral blood mononuclear cells. This clone demonstrated robust viral propagation and profound syncytium formation in CD4+, CXCR4-expressing human glioma NP-2 cells, indicating that p05MYKL045.1 is a CXCR4-using virus. Viral propagation, however, was not detected in various human T cell lines including MT-2, M8166, Sup-T1, H9, Jurkat, Molt-4 and PM1. p05MYKL045.1 appears to proliferate only in restricted host range, suggesting that unknown viral and/or cellular host factors may play a role in viral infectivity and replication in human T cell lines. Availability of a CRF33_01B molecular clone will be useful in facilitating the development of vaccine candidates that match the HIV-1 strains circulating in Southeast Asia.
  3. Tee KK, Takebe Y, Kamarulzaman A
    Int J Infect Dis, 2009 May;13(3):307-18.
    PMID: 19010076 DOI: 10.1016/j.ijid.2008.09.005
    Over the past decade, a number of unique zoonotic and non-zoonotic viruses have emerged in Malaysia. Several of these viruses have resulted in significant morbidity and mortality to those affected and they have imposed a tremendous public health and economic burden on the state. Amongst the most devastating was the outbreak of Nipah virus encephalitis in 1998, which resulted in 109 deaths. The culling of more than a million pigs, identified as the amplifying host, ultimately brought the outbreak under control. A year prior to this, and subsequently again in 2000 and 2003, large outbreaks of hand-foot-and-mouth disease due to enterovirus 71, with rare cases of fatal neurological complications, were reported in young children. Three other new viruses - Tioman virus (1999), Pulau virus (1999), and Melaka virus (2006) - whose origins have all been linked to bats, have been added to the growing list of novel viruses being discovered in Malaysia. The highly pathogenic H5N1 avian influenza has also been detected in Malaysia with outbreaks in poultry in 2004, 2006, and 2007. Fortunately, no human infections were reported. Finally, the HIV/AIDS epidemic has seen the emergence of an HIV-1 recombinant form (CRF33_01B) in HIV-infected individuals from various risk groups, with evidence of ongoing and rapid expansion.
  4. Tee KK, Li XJ, Nohtomi K, Ng KP, Kamarulzaman A, Takebe Y
    J Acquir Immune Defic Syndr, 2006 Dec 15;43(5):523-9.
    PMID: 17031320
    A molecular epidemiological investigation was conducted among various risk populations (n = 184) in Kuala Lumpur, Malaysia, in 2003 to 2005, on the basis of nucleotide sequences of protease and reverse transcriptase regions. In addition to circulating HIV-1 strains, including CRF01_AE (57.1%), subtype B (20.1%), and subtype C (0.5%), we detected a candidate with a new circulating recombinant form (CRF). We determined four near-full-length nucleotide sequences with identical subtype structure from epidemiologically unlinked individuals of different risk and ethnic groups. In this chimera, two short subtype B segments were inserted into the gag-RT region in a backbone of CRF01_AE. The recombinant structure was distinct from previously identified CRF15_01B in Thailand. In agreement with the current HIV nomenclature system, this constitutes a novel CRF (CRF33_01B). The overall prevalence of CRF33_01B is 19.0% (35/184). Although the prevalence of CRF33_01B is particularly high among injecting drug users (42.0%, 21/50), it is also detected in a substantial proportion of homo-/bisexual males (18.8%, 3/16) and heterosexuals (9.8%, 9/92). Moreover, unique recombinant forms composed of CRF01_AE and subtype B that have a significant structural relationship with CRF33_01B were detected in 1.6% (3/184) of study subjects, suggesting an ongoing recombination process in Malaysia. This new CRF seems to be bridging viral transmission between different risk populations in this country.
  5. Tee KK, Chan PQ, Loh AM, Singh S, Teo CH, Iyadorai T, et al.
    J Med Virol, 2023 Feb;95(2):e28520.
    PMID: 36691929 DOI: 10.1002/jmv.28520
    Pteropine orthoreovirus (PRV), an emerging bat-borne virus, has been linked to cases of acute respiratory infections (ARI) in humans. The prevalence, epidemiology and genomic diversity of PRV among ARI of unknown origin were studied. Among 632 urban outpatients tested negative for all known respiratory viruses, 2.2% were PRV-positive. Patients mainly presented with moderate to severe forms of cough, sore throat and muscle ache, but rarely with fever. Phylogenetic analysis revealed that over 90% of patients infected with the Melaka virus (MelV)-like PRV, while one patient infected with the Pulau virus previously found only in fruit bats. Human oral keratinocytes and nasopharyngeal epithelial cells were susceptible to clinical isolates of PRV, including the newly isolated MelV-like 12MYKLU1034. Whole genome sequence of 12MYKLU1034 using Nanopore technique revealed a novel reassortant strain. Evolutionary analysis of the global PRV strains suggests the continuous evolution of PRV through genetic reassortment among PRV strains circulating in human, bats and non-human primate hosts, creating a spectrum of reassortant lineages with complex evolutionary characteristics. In summary, the role of PRV as a common etiologic agent of ARI is evident. Continuous monitoring of PRV prevalence, pathogenicity and diversity among human and animal hosts is important to trace the emergence of novel reassortants.
  6. Tee KK, Bon AH, Chow WZ, Ng KT, Chan KG, Kamarulzaman A, et al.
    Genome Announc, 2017 Jun 29;5(26).
    PMID: 28663289 DOI: 10.1128/genomeA.00459-17
    We report here the first HIV-1 circulating recombinant form (CRF) complex identified among the blood donors in Malaysia. The CRF77_cpx mosaic genome consists of parental subtypes B', C, and CRF01_AE and is structurally related to CRF07_BC. The identification of CRF77_cpx underlines the genetic complexity and mobility of HIV-1 among the blood donors.
  7. Takebe Y, Tsujigiwa H, Katase N, Siar CH, Takabatake K, Fujii M, et al.
    J Oral Pathol Med, 2017 Jan;46(1):67-75.
    PMID: 27327904 DOI: 10.1111/jop.12467
    BACKGROUND: Tumor parenchyma-stromal interactions affect the properties of tumors and their dynamics. Our group previously showed that secreted frizzled related protein (sFRP)-2 impairs bone formation and promotes bone invasion in ameloblastoma. However, the effects of the secreted growth factors CCN2, TGF-β, and BMP4 on stromal tissues in ameloblastoma remain unclear.

    MATERIALS AND RESULTS: Thirty-five paraffin-embedded ameloblastoma cases, ameloblastoma-derived cell lines (AM-1), and primary cultures of ameloblastoma stromal fibroblasts (ASF) were used. Immunohistochemistry, MTT assay, Western blotting, and RT-PCR were performed on these samples. Parenchyma-stromal CCN2 overexpression correlated significantly with fibrous-type stroma, but not with myxoid-type stroma, suggesting a role of CCN2 in fibrosis (P < 0.05). Recombinant CCN2 induction of enhanced ASF proliferation in AM-1 medium supports this view. Conversely, BMP4 and TGF-β were expressed in myxoid-type fibroblasts, but little expression was found in parenchyma. RANKL-positive and CD68-positive stromal cell populations were significantly greater in myxoid-type tumor areas than in fibrous-type tumor areas, while a higher Ki-67 labeling index was recorded in ameloblastoma with fibrous-type stroma. These data suggest that stromal properties influence bone resorption-related activities and growth rates, respectively.

    CONCLUSIONS: These results suggest that the effects of secreted growth factors are governed by ameloblastoma parenchyma-stromal interactions. CCN2 promotes fibrogenesis independent of TGF-β signaling. Absence of CCN2 expression is associated with a phenotypic switch to a myxoid-type microenvironment that is conducive for TGF-β/BMP4 signaling to promote osteoclastogenesis.

  8. Supian NI, Ng KT, Chook JB, Takebe Y, Chan KG, Tee KK
    BMC Infect Dis, 2021 May 17;21(1):446.
    PMID: 34001016 DOI: 10.1186/s12879-021-06148-x
    BACKGROUND: Coxsackievirus A21 (CVA21), a member of Enterovirus C from the Picornaviridae family, has been associated with respiratory illnesses in humans.

    METHODS: A molecular epidemiological investigation of CVA21 was conducted among patients presenting with acute upper respiratory illnesses in the ambulatory settings between 2012 and 2014 in Kuala Lumpur, Malaysia.

    RESULTS: Epidemiological surveillance of acute respiratory infections (n = 3935) showed low-level detection of CVA21 (0.08%, 1.4 cases/year) in Kuala Lumpur, with no clear seasonal distribution. Phylogenetic analysis of the new complete genomes showed close relationship with CVA21 strains from China and the United States. Spatio-temporal mapping of the VP1 gene determined 2 major clusters circulating worldwide, with inter-country lineage migration and strain replacement occurring over time.

    CONCLUSIONS: The study highlights the emerging role of CVA21 in causing sporadic acute respiratory outbreaks.

  9. Oong XY, Ng KT, Takebe Y, Ng LJ, Chan KG, Chook JB, et al.
    Emerg Microbes Infect, 2017 Jan 04;6(1):e3.
    PMID: 28050020 DOI: 10.1038/emi.2016.132
    Human coronavirus OC43 (HCoV-OC43) is commonly associated with respiratory tract infections in humans, with five genetically distinct genotypes (A to E) described so far. In this study, we obtained the full-length genomes of HCoV-OC43 strains from two previously unrecognized lineages identified among patients presenting with severe upper respiratory tract symptoms in a cross-sectional molecular surveillance study in Kuala Lumpur, Malaysia, between 2012 and 2013. Phylogenetic, recombination and comparative genomic analyses revealed two distinct clusters diverging from a genotype D-like common ancestor through recombination with a putative genotype A-like lineage in the non-structural protein (nsp) 10 gene. Signature amino acid substitutions and a glycine residue insertion at the N-terminal domain of the S1 subunit of the spike gene, among others, exhibited further distinction in a recombination pattern, to which these clusters were classified as genotypes F and G. The phylogeographic mapping of the global spike gene indicated that the genetically similar HCoV-OC43 genotypes F and G strains were potentially circulating in China, Japan, Thailand and Europe as early as the late 2000s. The transmission network construction based on the TN93 pairwise genetic distance revealed the emergence and persistence of multiple sub-epidemic clusters of the highly prevalent genotype D and its descendant genotypes F and G, which contributed to the spread of HCoV-OC43 in the region. Finally, a more consistent nomenclature system for non-recombinant and recombinant HCoV-OC43 lineages is proposed, taking into account genetic recombination as an important feature in HCoV evolution and classification.
  10. Ng KT, Ong LY, Lim SH, Takebe Y, Kamarulzaman A, Tee KK
    PLoS One, 2013;8(6):e67286.
    PMID: 23840653 DOI: 10.1371/journal.pone.0067286
    HIV-1 epidemics among men who have sex with men (MSM) continue to expand in developed and developing countries. Although HIV infection in MSM is amongst the highest of the key affected populations in many countries in Southeast Asia, comprehensive molecular epidemiological study of HIV-1 among MSM remains inadequate in the region including in Malaysia. Here, we reported the phylodynamic profiles of HIV-1 genotypes circulating among MSM population in Kuala Lumpur, Malaysia. A total of n = 459 newly-diagnosed treatment-naïve consenting subjects were recruited between March 2006 and August 2012, of whom 87 (18.9%) were self-reported MSM. Transmitted drug resistance mutations were absent in these isolates. Cumulatively, phylogenetic reconstructions of the pro-rt gene (HXB2∶2253-3275) showed that HIV-1 subtype B and CRF01_AE were predominant and contributed to approximately 80% of the total HIV-1 infection among MSM. In addition to numerous unique transmission lineages within these genotypes, twelve monophyletic transmission clusters of different sizes (2-7 MSM sequences, supported by posterior probability value of 1) were identified in Malaysia. Bayesian coalescent analysis estimated that the divergence times for these clusters were mainly dated between 1995 and 2005 with four major transmission clusters radiating at least 12 years ago suggesting that active spread of multiple sub-epidemic clusters occurred during this period. The changes in effective population size of subtype B showed an exponential growth within 5 years between 1988 and 1993, while CRF01_AE lineage exhibited similar expansion between 1993 and 2003. Our study provides the first insight of the phylodynamic profile of HIV-1 subtype B and CRF01_AE circulating among MSM population in Kuala Lumpur, Malaysia, unravelling the importance of understanding transmission behaviours as well as evolutionary history of HIV-1 in assessing the risk of outbreak or epidemic expansion.
  11. Ng KT, Ong LY, Takebe Y, Kamarulzaman A, Tee KK
    J Virol, 2012 Oct;86(20):11405-6.
    PMID: 22997423
    We report here the first novel HIV-1 circulating recombinant form (CRF) 54_01B (CRF54_01B) isolated from three epidemiologically unlinked subjects of different risk groups in Malaysia. These recently sampled recombinants showed a complex genome organization composed of parental subtype B' and CRF01_AE, with identical recombination breakpoints observed in the gag, pol, and vif genes. Such a discovery highlights the ongoing active generation and spread of intersubtype recombinants involving the subtype B' and CRF01_AE lineages and indicates the potential of the new CRF in bridging HIV-1 transmission among different risk groups in Southeast Asia.
  12. Ng KT, Lee YM, Al-Darraji HA, Xia X, Takebe Y, Chan KG, et al.
    Genome Announc, 2013 Jan;1(1).
    PMID: 23409272 DOI: 10.1128/genomeA.00168-12
    We report the full genome sequence of hepatitis C virus (HCV) subtype 6n from Kuala Lumpur, Malaysia. Phylogenetic analysis of the isolate 10MYKJ032 suggests that Southeast Asia might be the origin for the HCV subtype 6n and highlights the possible spread of this lineage from Southeast Asia to other regions.
  13. Ng KT, Takebe Y, Chook JB, Chow WZ, Chan KG, Abed Al-Darraji HA, et al.
    Sci Rep, 2015;5:15198.
    PMID: 26459957 DOI: 10.1038/srep15198
    Co-infections with human immunodeficiency virus type 1 (HIV-1) and human pegivirus (HPgV) are common in hepatitis C virus (HCV)-infected individuals. However, analysis on the evolutionary dynamics and transmission network profiles of these viruses among individuals with multiple infections remains limited. A total of 228 injecting drug users (IDUs), either HCV- and/or HIV-1-infected, were recruited in Kuala Lumpur, Malaysia. HCV, HIV-1 and HPgV genes were sequenced, with epidemic growth rates assessed by the Bayesian coalescent method. Based on the sequence data, mono-, dual- and triple-infection were detected in 38.8%, 40.6% and 20.6% of the subjects, respectively. Fifteen transmission networks involving HCV (subtype 1a, 1b, 3a and 3b), HIV-1 (CRF33_01B) and HPgV (genotype 2) were identified and characterized. Genealogical estimates indicated that the predominant HCV, HIV-1 and HPgV genotypes were introduced into the IDUs population through multiple sub-epidemics that emerged as early as 1950s (HCV), 1980s (HIV-1) and 1990s (HPgV). By determining the difference in divergence times between viral lineages (ΔtMRCA), we also showed that the frequency of viral co-transmission is low among these IDUs. Despite increased access to therapy and other harm reduction interventions, the continuous emergence and coexistence of new transmission networks suggest persistent multiple viral transmissions among IDUs.
  14. Ng KT, Takebe Y, Kamarulzaman A, Tee KK
    Arch Virol, 2021 Jan;166(1):225-229.
    PMID: 33084935 DOI: 10.1007/s00705-020-04855-5
    Genome sequences of members of a potential fourth rhinovirus (RV) species, provisionally denoted as rhinovirus A clade D, from patients with acute respiratory infection were determined. Bayesian coalescent analysis estimated that clade D emerged around the 1940s and diverged further around 2006-2007 into two distinctive sublineages (RV-A8-like and RV-A45-like) that harbored unique "clade-defining" substitutions. Similarity plots and bootscan mapping revealed a recombination breakpoint located in the 5'-UTR region of members of the RV-A8-like sublineage. Phylogenetic reconstruction revealed the distribution of clade D viruses in the Asia Pacific region and in Europe, underlining its worldwide distribution.
  15. Ng KT, Oong XY, Lim SH, Chook JB, Takebe Y, Chan YF, et al.
    Clin Infect Dis, 2018 07 02;67(2):261-268.
    PMID: 29385423 DOI: 10.1093/cid/ciy063
    Background: Rhinovirus (RV) is one of the main viral etiologic agents of acute respiratory illnesses. Despite the heightened disease burden caused by RV, the viral factors that increase the severity of RV infection, the transmission pattern, and seasonality of RV infections remain unclear.

    Methods: An observational study was conducted among 3935 patients presenting with acute upper respiratory illnesses in the ambulatory settings between 2012 and 2014.

    Results: The VP4/VP2 gene was genotyped from all 976 RV-positive specimens, where the predominance of RV-A (49%) was observed, followed by RV-C (38%) and RV-B (13%). A significant regression in median nasopharyngeal viral load (VL) (P < .001) was observed, from 883 viral copies/µL at 1-2 days after symptom onset to 312 viral copies/µL at 3-4 days and 158 viral copies/µL at 5-7 days, before declining to 35 viral copies/µL at ≥8 days. In comparison with RV-A (median VL, 217 copies/µL) and RV-B (median VL, 275 copies/µL), RV-C-infected subjects produced higher VL (505 copies/µL; P < .001). Importantly, higher RV VL (median, 348 copies/µL) was associated with more severe respiratory symptoms (Total Symptom Severity Score ≥17, P = .017). A total of 83 phylogenetic-based transmission clusters were identified in the population. It was observed that the relative humidity was the strongest environmental predictor of RV seasonality in the tropical climate.

    Conclusions: Our findings underline the role of VL in increasing disease severity attributed to RV-C infection, and unravel the factors that fuel the population transmission dynamics of RV.

  16. Li Y, Tee KK, Liao H, Hase S, Uenishi R, Li XJ, et al.
    J Acquir Immune Defic Syndr, 2010 Jun;54(2):129-36.
    PMID: 20386110 DOI: 10.1097/QAI.0b013e3181d82ce5
    A molecular epidemiological investigation conducted among injecting drug users in eastern Peninsular Malaysia in 2007 identified a cluster of sequences (n = 3) located outside any known HIV-1 genotype. Analyses of near full-length nucleotide sequences of these strains from individuals with no recognizable linkage revealed that they have an identical subtype structure comprised of CRF01_AE and subtype B', distinct from any known circulating recombinant forms (CRFs). This novel CRF, designated CRF48_01B, is closely related to CRF33_01B, previously identified in Kuala Lumpur. Phylogenetic analysis of multiple CRF48_01B genome regions showed that CRF48_01B forms a monophyletic cluster within CRF33_01B, suggesting that this new recombinant is very likely a descendant of CRF33_01B. CRF48_01B thus represents one of the first examples of a "second-generation" CRF, generated by additional crossover with pre-existing CRFs. Corroborating these results, Bayesian molecular clock analyses indicated that CRF48_01B emerged in approximately 2001, approximately approximately 8 years after the emergence of CRF33_01B.
  17. Chow WZ, Nizam S, Ong LY, Ng KT, Chan KG, Takebe Y, et al.
    Genome Announc, 2014;2(2).
    PMID: 24675847 DOI: 10.1128/genomeA.00139-14
    A complex HIV-1 unique recombinant form involving subtypes CRF01_AE, B, and B' was recently identified from an injecting drug user in Malaysia. A total of 13 recombination breakpoints were mapped across the near-full-length genome of isolate 10MYPR226, indicating the increasingly diverse molecular epidemiology and frequent linkage among various high-risk groups.
  18. Chow WZ, Al-Darraji H, Lee YM, Takebe Y, Kamarulzaman A, Tee KK
    J Virol, 2012 Oct;86(20):11398-9.
    PMID: 22997419
    A novel HIV-1 genotype designated CRF53_01B was recently characterized from three epidemiologically unrelated persons in Malaysia. Here we announced three recently isolated full-length genomes of CRF53_01B, which is likely to be phylogenetically linked to CRF33_01B, circulating widely in Southeast Asia. The genome sequences may contribute to HIV-1 molecular surveillance and future vaccine development in the region.
  19. Chow WZ, Lim SH, Ong LY, Yong YK, Takebe Y, Kamarulzaman A, et al.
    PLoS One, 2015;10(9):e0137281.
    PMID: 26335136 DOI: 10.1371/journal.pone.0137281
    Human immunodeficiency virus type 1 (HIV-1) subtypes have been shown to differ in the rate of clinical progression. We studied the association between HIV-1 subtypes and the rate of CD4+ T-cell recovery in a longitudinal cohort of patients on combination antiretroviral therapy (cART). We studied 103 patients infected with CRF01_AE (69%) and subtype B (31%) who initiated cART between 2006 and 2013. Demographic data, CD4+ T-cell counts and HIV-1 viral load were abstracted from patient medical charts. Kaplan-Meier was used to estimate the time to CD4+ T-cell count increase to ≥350 between subtypes and effects of covariates were analysed using Cox proportional hazards. An 87% of the study population were male adults (mean age of 38.7 years old). Baseline CD4+ T-cell counts and viral loads, age at cART initiation, sex, ethnicity and co-infection did not differ significantly between subtypes. A shorter median time for CD4+ T-cell count increase to ≥350 cells/μL was observed for CRF01_AE (546 days; 95% confidence interval [CI], 186-906 days; P = .502) compared to subtype B (987 days; 95% CI, 894-1079 days). In multivariate analysis, female sex was significantly associated with a 2.7 times higher chance of achieving CD4+ T-cell recovery (adjusted hazard ratio [HR], 2.75; 95% CI, 1.21-6.22; P = .025) and both baseline CD4+ T-cell count (P = .001) and viral load (P = .001) were important predictors for CD4+ T-cell recovery. Immunological recovery correlated significantly with female sex, baseline CD4+ T-cell counts and viral load but not subtype.
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